Axon Guidance 2024 BIO 344 PDF

Development of the Nervous System HS2024 BIO 344 Esther Stoeckli Dept. of Molecular Life Sciences University of Zurich The complexity of axon tracts increases rapidly during early stages of developmen...

Development of the Nervous System HS2024 BIO 344 Esther Stoeckli Dept. of Molecular Life Sciences University of Zurich The complexity of axon tracts increases rapidly during early stages of development Sanes, Reh, Harris, 2006 The history of axon guidance Santiago Ramón y Cajal growth cone Paul Weiss contact guidance by mechanical means Roger Sperry chemoaffinity hypothesis Inputs from the retina form a topographic map in the tectum Purves and Lichtman, 1985  Inputs from the retina form a topographic map in the tectum Sanes, Reh, Harris, 2006  Inputs from the retina form a topographic map in the tectum Sanes, Reh, Harris, 2006 Sperry‘s chemoaffinity hypothesis: The specificity of axonal connections within a neural map is determined by molecular tags (address labels) on projecting axons and their target cells.  ? What are these molecular tags and how do axons find their target ?  ? What are these molecular tags see next week’s lecture ?  ? What are these molecular tags and how do axons find their target ? Follow the one that knows how to get there ! The labeled-pathway hypothesis Solve a big problem by cutting it down to little steps  Navigation depends on landmarks and information about direction Sanes, Reh, Harris, 2006  The same is true for the developing nervous system Sanes, Reh, Harris, 2006  Axons use guidepost cells as intermediate targets Bentley and O‘Connor, 1992 Towards the molecular basis of axon guidance.... Growth cones readily grow onto a more attractive substrate Raper and colleagues Observation by Paul Letourneau: Axons seem to select their pathway according to adhesive strength Letourneau Dev. Biol., 1975 Are these observations still true with more physiological substrates? Sanes, Reh, Harris, 2006 Are these observations still true with more physiological substrates? Sanes, Reh, Harris, 2006 The strength of adhesion does not correlate with growth rate or preference ! Lemmon et al., J. Neuroscience 12(1992)818-826 Still, adhesion does play a role in axon guidance... Still, adhesion does play a role in axon guidance... How about the opposite? Growth cones of PNS axons collapse upon contact with CNS axons Kapfhammer and Raper, 1986 DRG growth cones collapse after addition of Sema3A to the medium Raper and colleagues Semaphorin3A repels NGF-dependent sensory axons radial outgrowth of DRG axons with control COS cells Semaphorin3A repels DRG axons Sanes, Reh, Harris, 2006 Axon guidance – a cooperation of attractive and repulsive cues Building Brains, Price et al., 2011 Information derived from the interaction of surface receptors with guidance cues is transmitted to the cytoskeleton Dickson, 2002 Which molecules act as guidance cues (or their receptors)? How many are there? Do all axons listen to the same guidance cues? Axons are guided by a combination of positive and negative guidance cues Commissural neurons in the dorsal spinal cord – the dI1 subpopulation Drawing by Ramón y Cajal Netrin is a chemoattractant for commissural axons Tessier-Lavigne and colleagues ….and there are additional cues expressed in the floor plate Shh acts as an attractant Charron et al., Cell 2003 VEGF acts as attractant Ruiz de Almodovar, Neuron 2011  Commissural axons are repelled by the roof plate Augsburger et al., Neuron 1999  Commissural axons are repelled by the roof plate Augsburger et al., Neuron 1999  BMP7 mimicks the effect of the roof plate Augsburger et al., Neuron 1999 Draxin is expressed by the roof plate and repels commissural axons Islam et al., Science 2009 What about short-range guidance cues? The interaction between growth cone Axonin-1 and floor-plate NrCAM makes axons enter the floor plate Stoeckli & Landmesser, Neuron 1995 NrCAM expressed by floor-plate cells is a binding partner for Axonin-1 in commissural axon guidance Stoeckli & Landmesser, Neuron 1995 Fasciculation is not required for commissural axon pathfinding in higher vertebrates control without Axonin-1 without NgCAM Stoeckli & Landmesser, Neuron 1995 Why do commissural axons ever leave the floor plate? Target The intermediate target looses ist attractiveness Target Commissural axons loose responsiveness to Netrin after contact with the floor plate Shirasaki et al., Science, 1998 Shirasaki et al., Science, 1998 Commissural axons loose responsiveness to Netrin after contact with the floor plate Building Brains, Price et al., 2011 The midline glia in the ventral nerve cord is the equivalent of the floor plate in vertebrates Building Brains, Price et al., 2011 Midline-derived guidance cues in the ventral nerve cord Building Brains, Price et al., 2011 A screen for midline crossing mutants in Drosophila led to the identification of commissureless and roundabout Seeger et al., 1993 Kidd et al., 1998 The balance between positive and negative signals is shifted upon floor-plate contact - - + -- RabGDI is required for Robo1 insertion into the growth cone membrane Robo Robo & RabGDI Philipp et al., Neural Development 2012 Trafficking is an important regulator of protein expression on the growth cone surface kinesin - anterograde dynein - retrograde Building Brains, Price et al., 2011 How do axons switch their behavior at an intermediate target? by changing guidance receptors on the growth cone change transcription change translation change transport/trafficking change stability change function/availability  (Classical) Guidance cues for commissural axons long-range: short-range: BMP/Draxin Contactin-2(Axonin-1) BMPR NrCAM DCC Robo Slit SynCAMs Netrin/Shh/VEGF Sema6B/PlexinAs Nrp2/Sema3 DCC F-Spondin Ptc/Boc/Smo MDGA2 Flk Nectins De Ramon Francàs et al., Dev Biol. 2017 Commissural axons turn rostrally upon floor-plate exit from Lyuksyutova et al., 2003 Wnts are expressed in a decreasing rostral to caudal gradient from Lyuksyutova et al., 2003  Wnt4 is an attractant for post-crossing commissural axons Lyuksyutova et al., 2003 Charron and Tessier-Lavigne, 2005 Sonic hedgehog guides commissural axons along the longitudinal axis of the spinal cord control dsSHH Bourikas et al., 2005 Wnt4 attracts and Shh repels postcommissural axons Charron and Tessier-Lavigne, 2005 Shh acts as a morphogen Briscoe, 2009 Shh acts as a chemoattractant for pre-crossing axons Charron and Tessier-Lavigne, Development 2005 Shh acts as a repellent cue for post-crossing commissural axons Bourikas, D., Pekarik, V., Baeriswyl, T., Grunditz, A., Sadhu, R., Nardo, M., and Stoeckli, E.T. (2005) Nature Neurosci. 8: 297-304 Commissural axons change the Shh receptor at the midline Boc/ Ptc/Smo Hhip Shh = + Shh = - Bourikas et al., Nat. Neuroscience 8(2005)297-304 Glypican1 mediates the switch in commissural axons‘ responsiveness to Shh at the midline Ptc/Smo Boc/Ptc/Smo GPC1 Hhip Shh = + Shh = - Wilson and Stoeckli, Neuron 79(2013)478-491 Sfrp1 forms a Wnt activity gradient along the chicken spinal cord Wnt activity Wnt protein ^ = Sfrp1 Domanitskaya, Wacker et al., J. Neurosci. 2010 Shh guides postcommissural axons both directly and indirectly by regulating Wnt activity ^ = + R + _ C activity protein Sfrp Shh Shh Wnt Wnt Domanitskaya, Wacker et al., J. Neurosci. 2010 Why do axons only turn after contact with the intermediate target? by changing guidance receptors on the growth cone changes in transcription changes in translation changes of transport/trafficking changes of protein stability changes of protein function/availability  Why do axons only turn after contact with the intermediate target? by changing guidance receptors on the growth cone changes in transcription changes in translation Robo changes of transport/trafficking changes of protein stability changes of protein function/availability Why do axons only turn after contact with the intermediate target? by changing guidance receptors on the growth cone Hhip changes in transcription changes in translation Frz3 changes of transport/trafficking changes of protein stability changes of protein function/availability Why do axons only turn after contact with the intermediate target? by changing guidance receptors on the growth cone changes in transcription changes in translation changes of transport/trafficking changes of protein stability changes of protein function/availability PlexinA1 is stabilized in an NrCAM- & Gdnf-dependent manner on the way to the floor plate Calpain PlexinA1 Sema3B Calpain PlexinA1 Sema3B NrCAM & Gdnf Charoy et al., Neuron 75(2012)1051 Nawabi et al., Genes Dev 24(2010)396 Why do axons only turn after contact with the intermediate target? by changing guidance receptors on the growth cone changes in transcription changes in translation changes of transport/trafficking changes of protein stability changes of protein function/availability Cis- versus trans-interactions can change trans-interactions Andermatt et al., Development 141(2014)3709 Why do axons only turn after contact with the intermediate target? by changing guidance receptors on the growth cone changes in transcription changes in translation changes of transport/trafficking changes of protein stability changes of protein function/availability The miR124 is a timer for the sensitivity of retinal ganglion cell axons to Sema3A Baudet et al., Nature Neurosci 15(2012)29  miR-124 regulates the responsiveness to Sema3a young RGC older RGC miR-124 miR-124 CoREST CoREST Repressor Repressor Nrp1 Nrp1 no response to response Sema3A Sema3A Baudet et al., Nature Neurosci 15(2012)29 The balance between positive and negative signals is shifted upon floor-plate contact - - + -- At floorplate entry, commissural growth cones express Axonin-1/Contactin-2 to detect NrCAM At this time, RabGDI is upregulated at the transcriptional level RabGDI expression results in the trafficking of Robo1 to the growth cone surface Robo1 expression on the growth cone surface pushes growth cones out of the floorplate due to the gain in responsiveness to Slit Cables1 links Slit/Robo signaling to Wnt signaling by transfer of Abl kinase from Robo1 to β-Catenin responsiveness to the Wnt gradient requires phosphorylation of β-Catenin at tyrosine 489 Zuñiga et al., Development 2023 What about wiring the brain? Stoeckli Development 145(2018) pii: dev151415 Summary: Axons navigate from one intermediate target (choice point) to the next until they reach their final target Axons are guided through the pre-existing tissue by a combination of short- and long-range guidance cues that interact with specific receptors on the growth cone surface The type of receptor expressed on the growth cone surface determines whether a guidance cue is attractive or repulsive Crosstalk between guidance receptors and cytoskeleton induces growth cone behavior At each intermediate target/choice point growth cones switch responsiveness to move on Changes in surface receptors are regulated at different levels and require precise timing